Protein kinase C is a calcium and phospholipid activated enzyme that plays a significant role in mediating the effects of a host of hormones, neurotransmitters, growth factors, antigens, and inflammatory mediators (Nishizuka, Y. (1988) Nature, 334:661). When these extracellular agents bind to their specific cell surface receptors, they stimulate the hydrolysis of phosphatidylinositol, phosphatidylcholine, or phosphatidylethanolamine, resulting in the accumulation of diacylglycerol which activates protein kinase C. This activation of PKC causes specific cellular substrates to be phosphorylated, resulting in the regulation of cellular processes which are closely linked to the physiological control of contractile, secretory, and proliferative processes (Nishizuka, Y. (1984) Nature, 308: 693). As examples of physiological response induced by the system in which protein kinase C participates, there have been reported serotonin release from platelets (Kaibuchi, et al. (1982) Cell Calcium, 3:323; Kaibuchi, et al. (1985) J. Biol. Chem., 258:6701), lysosomal enzyme release and superoxide generation from neutrophils (Kajikawa, et al. (1983) Biochem. Biophys. Res. Commun.; 116:743; Sehau, et al. (1983) Biochem. Biophys. Acta, 762:420), histamine release from mast cells (Kata Kami, et al. (1982) Biochem. Biphys- Res. Commun., 121:573), secretion of aldosterone from adrenal glomerulus (Kojima, et al. (1983) Biochem Biophys. Res Commun., 116:555), and contraction of vascular smooth muscle (Rasmussen, et al. (1984) Biochem. Biophys. Res. Commun., 122:776. Thus, it has been demonstrated that protein kinase C takes part in many important physiological responses in vivo. Therefore, an inhibitor of protein kinase C would be expected to be useful in the treatment of cardiovascular and renal disorders, inflammation, immunosuppression, septic shock and central nervous system disorders.
It has now been found that certain 4,5,6,7-tetrahydropyrrolo (2, 3-c) azepine-8-ones previously described as alpha-adrenoceptor blocking agents and antineoplastic agents are also protein kinase C inhibitors and hence are expected to have utility in the treatment of conditions wherein protein kinase C inhibition is indicated.